Discovery and Optimization of Tau Targeted Protein Degraders Enabled by Patient Induced Pluripotent Stem Cells-Derived Neuronal Models of Tauopathy
M. Catarina Silva,Ghata Nandi,Katherine A. Donovan,Quan Cai,Bethany C Berry,Radosław P. Nowak,Eric S. Fischer,Nathanael S. Gray,Fleur M. Ferguson,Stephen J. Haggarty +9 more
TLDR
The screening goal was to establish structure-activity relationships (SAR) for the different chemical series to identify the molecular composition that most efficiently led to tau degradation in human FTD ex vivo neurons, and the identification of the lead compound QC-01-175 and follow-up optimization strategies for this molecule are described.Abstract:
Accumulation of misfolded, aggregating proteins concurrent with disease onset and progression is a hallmark of neurodegenerative proteinopathies. An important class of these are tauopathies, such as frontotemporal dementia (FTD) and Alzheimer’s disease (AD), associated with accumulation of aberrant forms of tau protein in the brain. Pathological tau undergoes abnormal post-translational modifications, misfolding, oligomerization and changes in solubility, cellular redistribution, and spreading. Development and testing of experimental therapeutics that target these pathological tau conformers requires use of cellular models that recapitulate neuronal endogenous, non-heterologous tau expression under genomic and physiological contexts relevant to disease. In this study, we employed FTD-patient induced pluripotent stem cells (iPSC)-derived neurons, expressing a tau variant or mutation, as primary models for driving a medicinal chemistry campaign around tau targeting degrader series. Our screening goal was to establish structure-activity relationships (SAR) for the different chemical series to identify the molecular composition that most efficiently led to tau degradation in human FTD ex vivo neurons. We describe the identification of the lead compound QC-01-175 and follow-up optimization strategies for this molecule. We present three final lead molecules with tau degradation activity in mutant neurons, which establishes potential disease relevance and will drive future studies on specificity and pharmacological properties.read more
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Targeted Dephosphorylation of Tau by Phosphorylation Targeting Chimeras (PhosTACs) as a Therapeutic Modality.
TL;DR: In this paper , small molecule-based PhosTACs were used to recruit tau to PP2A, a native tau phosphatase, and induced the formation of a stable ternary complex, leading to rapid, efficient, and sustained tau dephosphorylation.
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Conserved gene signatures shared among MAPT mutations reveal defects in calcium signaling
M. Minaya,Sidharth Mahali,Abhirami K. Iyer,Abdallah M. Eteleeb,Rita Martinez,Guangming Huang,John P. Budde,Sally Temple,Alissa L. Nana,William W. Seeley,Salvatore Spina,Lea T. Grinberg,Oscar Harari,Celeste M. Karch +13 more
TL;DR: It is demonstrated that iPSC-derived neurons capture molecular processes that occur in human brains and can be used to pinpoint common molecular pathways involving synaptic and endolysosomal function and neuronal development, which may be regulated by disruptions in calcium homeostasis.
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Design, Synthesis and In Vitro Investigation of Cabozantinib-Based PROTACs to Target c-Met Kinase
A. A. Sachkova,Daria V. Andreeva,Alexander S. Tikhomirov,Alexander M. Scherbakov,D.I. Salnikova,Danila V. Sorokin,Fedor B Bogdanov,Yulia D. Rysina,Andrey E. Shchekotikhin,Ekaterina S. Shchegravina,Alexey Yu. Fedorov +10 more
TL;DR: In this paper , a series of c-Met-targeting cabozantinib-based PROTACs were developed, bearing a VHL-ligand as an E3-ligase binding moiety and glycol-based linkers.
Journal ArticleDOI
Involvement of heterologous ubiquitination including linear ubiquitination in Alzheimer’s disease and amyotrophic lateral sclerosis
Yusuke Sato,Seigo Terawaki,Daisuke Oikawa,Kouhei Shimizu,Yoshinori Okina,H. Ito,Fuminori Tokunaga +6 more
TL;DR: In this article , the linear ubiquitin chain assembly complex (LUBAC)-mediated Met1-linked linear UCLU chain, which activates the canonical NF-κB pathway, is also involved in cytoplasmic inclusions of tau in AD and TAR DNA-binding protein 43 in ALS.
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Mechanistic Studies and a Retrospective Cohort Study: The Interaction between PPAR Agonists and Immunomodulatory Agents in Multiple Myeloma
TL;DR: In this article , the effects and mechanisms underlying the drug-to-drug interactions between IMiDs and peroxisome proliferator-activated receptor (PPAR) agonists in multiple myeloma (MM) were analyzed.
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